Cirrhosis is the tenth leading cause of death in US males. Recent research has provided significant information regarding the molecular and cellular basis for the development of hepatic fibrosis-a reversible condition-that can lead to cirrhosis, hepatocellular carcinoma, and need for liver transplantation. Our preliminary data and the current proposal are consistent with the long-term objectives of this laboratory: to understand basic mechanisms associated with chronic liver wound-healing. Adiponectin promotes a molecular environment in hepatic stellate cells (HSCs)-e.g. reduced tissue inhibitor of metalloproteinase I [TIMP-I] expression that would favor dissolution of dense extracellular matrix, the basis for the pathogenesis of cirrhosis. In vitro adiponectin treated hepatic stellate cells (HSCs) block leptin-mediated signal transduction that leads to pro- fibrogenic responses in culture and, this inhibitory activity requires the adiponectin R1 receptor but does not appear to depend on adenosine monophosphate kinase (AMPK). The overall goal of the current proposal is to determine the molecular mechanisms whereby adiponectin is protective against hepatic fibrosis and can promote resolution of dense matrix since evidence exists that advanced fibrosis is reversible and mechanisms other than HSC apoptosis may contribute to fibrosis resolution. The hypothesis of this competing renewal: adiponectin promotes the resolution of hepatic fibrosis by inhibiting activation of focal adhesion kinase (FAK), preventing formation of focal adhesions (FA) which results in the suppression of key fibrogenic properties of the activated HSC. This hypothesis will be tested by three specific aims: SPECIFIC AIM 1: To demonstrate that adiponectin suppresses FAK activation in activated hepatic stellate cells (HSCs) thereby prohibiting focal adhesion (FA) formation and reducing markers of hepatic fibrosis. Preliminary data indicate that FAK phosphorylation is prevented in adiponectin-treated HSCs; and FAs are disrupted both in vitro and in vivo by adiponectin rescue in adiponectin knockout mice (Ad -/- mice). SPECIFIC AIM 2: To elucidate the molecular mechanism(s) of adiponectin-associated increase in MMP-1 and MMP-13 activity by examining transcriptional, post-transcriptional, and post-translational regulation. Preliminary data indicate that adiponectin treated HSCs induce a pattern of gene and protein expression (decreased TIMP-1, increased expression of MMP-1 and MMP-13) favorable to degradation of dense extracellular matrix (ECM).SPECIFIC AIM 3: To demonstrate the role of adiponectin in suppression of FAs and to ascertain the relationship between adiponectin delivery and reversal or senescence of the activated HSC phenotype. We will use Ad -/- mice subjected to either CCl4 or common bile-duct ligation (CBDL) for induction of fibrosis and administer recombinant adiponectin. Preliminary data indicate that Ad-/- mice treated with CCl4 have significant classic FAs that are disrupted by adiponectin delivery; and ex vivo, activated HSCs from these mouse lysates have suppressed ?-smooth muscle actin (?-SMA) expression.